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1.
Joo-Yong Lee Eunsil Cho Tae-Youn Kim Dong-Kyu Kim Richard D. Palmiter Irene Volitakis Jong S. Kim Ashley I. Bush Jae-Young Koh 《Biometals》2010,23(6):1085-1095
Both apolipoprotein E (apoE) and zinc are involved in amyloid β (Aβ) aggregation and deposition, in the hallmark neuropathology
of Alzheimer’s disease (AD). Recent studies have suggested that interaction of apoE with metal ions may accelerate amyloidogenesis
in the brain. Here we examined the impact of apoE deficiency on the histochemically reactive zinc pool in the brains of apoE
knockout mice. While there was no change in total contents of metals (zinc, copper, and iron), the level of histochemically
reactive zinc (principally synaptic zinc) was significantly reduced in the apoE-deficient brain compared to wild-type. This
reduction was accompanied by reduced expressions of the presynaptic zinc transporter, ZnT3, as well as of the δ-subunit of
the adaptor protein complex-3 (AP3δ), which is responsible for post-translational stability and activity of ZnT3. In addition,
the level of histochemically reactive zinc was also decreased in the cerebrovascular micro-vessels of apoE-deficient mice,
the site of cerebral amyloid angiopathy in AD. These results suggest that apoE may affect the cerebral free zinc pool that
contributes to AD pathology. 相似文献
2.
Alzheimer’s disease is characterised by the inappropriate death of brain cells and accumulation of the Aβ peptide in the brain.
Thus, it is possible that there are fundamental differences between Alzheimer’s disease patients and healthy individuals in
their abilities to clear Aβ from brain fluid and to protect neurons from Aβ toxicity. In the present study, we examined (1)
the cytotoxicity of Alzheimer’s disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer’s
disease and control CSF to protect cells from Aβ toxicity and to promote cell-mediated clearance of Aβ and lastly (3) the
effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer’s disease CSF samples
tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer’s disease CSF samples tested
were less able to protect cells from Aβ-induced toxicity and less efficient at promoting macrophage-like cell uptake when
compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin,
haptoglobin and α2-macroglobulin into CSF protected neuroblastoma cells from Αβ1-42 toxicity and promoted Αβ1-42 uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system
of extracellular protein folding quality control that protects against Aβ toxicity and accumulation. 相似文献
3.
The use of acetylcholinesterase inhibitors to decrease the breakdown of the neurotransmitter acetylcholine has been the main
symptomatic therapy for mild to moderate Alzheimer’s patients, though the etiology of Alzheimer’s disease remains unclear
and seems to involve multiple factors. Further evidence has indicated that some of these acetylcholinesterase inhibitors also
have non-cholinergic functions on the pathogenesis of Alzheimer’s disease including the formation and deposition of β-amyloid.
Huperzine A, a potent and reversible inhibitor of acetylcholinesterase that was initially isolated from a Chinese herb, has
been found to improve cognitive deficits in a broad range of animal models and has been used for Alzheimer’s disease treatment
in China. The novel neuroprotective effects of huperzine A might yield beneficial effects in Alzheimer’s disease therapy and
provide a potential template for the design of new selective and powerful anti-Alzheimer’s drugs. The present paper gives
an overview on the neuroprotective effects of huperzine A beyond its acetylcholinesterase inhibition. These effects include
regulating β-amyloid precursor protein metabolism, protecting against β-amyloid-mediated oxidative stress and apoptosis. The
structure–function relationship of huperzine A is also discussed. 相似文献
4.
Giordano V Peluso G Iannuccelli M Benatti P Nicolai R Calvani M 《Neurochemical research》2007,32(4-5):555-567
Since its definition Alzheimer’s disease has been at the centre of consideration for neurologists, psychiatrists, and pathologists.
With John P. Blass it has been disclosed a different approach Alzheimer’s disease neurodegeneration understanding not only
by the means of neurochemistry but also biochemistry opening new scenarios in the direction of a metabolic system degeneration.
Nowadays, the understanding of the role of cholesterol, insulin, and adipokines among the others in Alzheimer’s disease etiopathogenesis
is clarifying approaches valuable not only in preventing the disease but also for its therapy.
Special issue dedicated to John P. Blass. 相似文献
5.
Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder leading invariably to death, usually within
7–10 years after diagnosis and is the leading cause of dementia in the elderly. Not only is Alzheimer’s disease a tragic disease
in which people suffer from neurodegeneration in the years to come, it also becomes an incredible burden on the public health
system. However, there is currently no effective treatment to halt the progression or prevent the onset of Alzheimer’s disease.
This is partly due to the fact that the complex pathophysiology of Alzheimer’s disease is not yet completely understood. Recently,
Golgi apparatus is found to play an important role in Alzheimer’s disease. In this review, we discuss the changes of Golgi
apparatus during clinical progression and pathological development of Alzheimer’s disease. First, changes of Golgi apparatus
size in Alzheimer’s disease are summarized. We then address the role of Golgi apparatus in the neuropathology of Alzheimer’s
disease. Finally, the role of Golgi apparatus in the pathogenesis of Alzheimer’s disease is discussed. Understanding the contribution
of Golgi apparatus dysfunction to Alzheimer’s disease and its pathophysiological basis will significantly impact our ability
to develop more effective therapies for Alzheimer’s disease. 相似文献
6.
A. L. Schwarzman S. V. Sarantseva O. L. Runova E. I. Talalaeva M. P. Vitek 《Biophysics》2010,55(5):760-764
Experimental evidence has been obtained that mutations in the presenilin 1 (PS1) gene in familial Alzheimer’s disease can
lead to the disturbance of cell adhesion in model cell cultures. It was shown that, in L fibroblasts of mice with stable expression
of GFP-PS1 cDNA containing G209V or E319G mutations, cell-cell interactions and the accumulation of GFP-PS1 cDNA in intercellular
contacts are disturbed. Similar results were obtained in transfected human epithelial HEp2 cells. It is assumed that mutations
in familial Alzheimer’s disease lead to the disturbance of the functions of presenelin 1 in cell adhesion. 相似文献
7.
Matthew Schrag April Dickson Arshad Jiffry David Kirsch Harry V. Vinters Wolff Kirsch 《Biometals》2010,23(6):1123-1127
Reports that iron, zinc and copper homeostasis are in aberrant homeostasis are common for various neurodegenerative diseases,
particularly for Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. Manipulating the levels of these elements
in the brain through the application of chelators has been and continues to be tested therapeutically in clinical trials with
mixed results. Much of the data indicating that these metals are abnormally concentrated in Alzheimer’s disease and Parkinson’s
disease brain tissue was generated through the analysis of post-mortem human tissue which was archived in formalin. In this
study, we evaluated the effect of formalin fixation of brain on the levels of three important transition metals (iron, copper,
and zinc) by atomic absorption spectroscopy. Paired brain specimens were obtained at autopsy for each case; one was conserved
by formalin archival (averaging four years), the other was rapidly frozen. Both white and grey matter samples were analyzed
and the concentrations of iron and zinc were found to decrease with fixation. Iron was reduced by 40% (P < 0.01), and zinc by 77% (P < 0.0001); copper concentrations increased by 37% (P < 0.05) by the paired T-test. The increase in copper is likely due to contamination from trace copper in the formalin. These
results indicate that transition metal data obtained from fixed tissue may be heavily distorted and care should be taken in
interpreting this data. 相似文献
8.
Schliebs R 《Neurochemical research》2005,30(6-7):895-908
Alzheimer’s disease, the most common neurodegenerative disorder of senile dementia, is characterized by two major morpho-pathological
hallmarks. Deposition of extracellular neuritic, β-amyloid peptide-containing plaques (senile plaques) in cerebral cortical
regions of Alzheimer patients is accompanied by the presence of intracellular neurofibrillary tangles in cerebral pyramidal
neurons. Basal forebrain cholinergic dysfunction is also a consistent feature of Alzheimer’s disease, which has been suggested
to cause, at least partly, the cognitive deficits observed in patients with Alzheimer’s disease. Impaired cortical cholinergic
neurotransmission may also contribute to β-amyloid plaque pathology in Alzheimer’s disease by affecting expression and processing
of the β-amyloid precursor protein (APP). Vice versa, low level of soluble β-amyloid has been observed to inhibit cholinergic
synaptic function. Deposition of β-amyloid plaques in Alzheimer’s disease is also accompanied by a significant plaque-associated
glial up-regulation of interleukin-1, which has been attributed to affect expression and metabolism of APP and to interfere
with cholinergic transmission. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic
dysfunction, β-amyloid formation and deposition, as well as local inflammatory upregulation, would allow to derive potential
treatment strategies to pharmacologically intervene in the disease-causing signaling cascade. 相似文献
9.
10.
Summary. The pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, has been linked to a condition of oxidative
and nitrosative stress, arising from the imbalance between increased reactive oxygen species (ROS) and reactive nitrogen species
(RNS) production and antioxidant defences or efficiency of repair or removal systems. The effects of free radicals are expressed
by the accumulation of oxidative damage to biomolecules: nucleic acids, lipids and proteins. In this review we focused our
attention on the large body of evidence of oxidative damage to protein in Alzheimer’s disease brain and peripheral cells as
well as in their role in signalling pathways. The progress in the understanding of the molecular alterations underlying Alzheimer’s
disease will be useful in developing successful preventive and therapeutic strategies, since available drugs can only temporarily
stabilize the disease, but are not able to block the neurodegenerative process. 相似文献
11.
Zinc enriched (ZEN) neurons and terminals are abundant in the rodent spinal cord. Zinc ions have been suggested to modulate
the excitability of primary afferent fibers believed to be important in nociceptive transmission. To test the hypothesis that
vesicular zinc concentration is related to neuropathic pain we applied Chung’s rodent pain model on BALB/c mice, and traced
zinc transporter 3 (ZnT3) proteins and zinc ions with immunohistochemistry and autometallography (AMG), respectively. Under
anesthesia the left fifth lumbar spinal nerve was ligated in male mice in order to produced neuropathic pain. The animals
were then sacrificed 5 days later. The ZnT3 immunoreactivity was found to have decreased significantly in dorsal horn of fourth,
fifth, and sixth lumbar segments. In parallel with the depressed ZnT3 immunoreactivity the amount of vesicular zinc decreased
perceptibly in superficial gray matters of especially layer I-IV of the same segments. The transection-induced reduction of
vesicular zinc in ZEN terminals of the dorsal horn was synchronic to reduced pain threshold, as measured by von Frey method.
In a separate study, we observed intensive zinc selenite precipitation in somata of the smaller spinal ganglion cell, but
5 days after spinal nerve transection zinc precipitation was also found in the lager ganglion cells. The present results indicate
that zinc may be involved in pain mechanism in the spinal ganglion level. These results support the hypothesis that vesicular
zinc might have a modulatory role for neuropathic pain. Thus, increased pain sensitivity might be related to reduce vesicular
zinc level in the dorsal spinal gray matter. 相似文献
12.
13.
P. Eikelenboom J. M. Rozemuller G. Kraal F. C. Stam P. A. McBride M. E. Bruce H. Fraser 《Virchows Archiv. B, Cell pathology including molecular pathology》1991,60(1):329-336
Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer’s
disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement
receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates
a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation
or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer’s disease. Cerebral amyloid plaques in scrapie-affected
mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial
cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive
inflammatory process by β/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not
support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer’s disease.
This study was partly supported by a grant from the Praeventiefonds, project 28–1945 相似文献
14.
Ari M. Chow Philip Mok Dawn Xiao Sam Khalouei Ian R. Brown 《Cell stress & chaperones》2010,15(5):545-553
Human neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis have
been termed “protein misfolding disorders.” Upregulation of heat shock proteins that target misfolded aggregation-prone proteins
has been proposed as a potential therapeutic strategy to counter neurodegenerative disorders. The heat shock protein 70 (HSP70)
family is well characterized for its cytoprotective effects against cell death and has been implicated in neuroprotection
by overexpression studies. HSP70 family members exhibit sequence and structural conservation. The significance of the multiplicity
of HSP70 proteins is unknown. In this study, coimmunoprecipitation was employed to determine if association of HSP70 family
members occurs, including Hsp70B′ which is present in the human genome but not in mouse and rat. Heteromeric complexes of
Hsp70B′, Hsp70, and Hsc70 were detected in differentiated human SH-SY5Y neuronal cells. Hsp70B′ also formed complexes with
Hsp40 suggesting a common co-chaperone for HSP70 family members. 相似文献
15.
Alzheimer’s disease is characterized pathologically by senile plaques in the brain. The major component of senile plaques
is amyloid-β (Aβ), which is cleaved from Alzheimer’s Aβ protein precursor (AβPP). Recently, information regarding the cytoplasmic
tail of AβPP has started to emerge, opening up various insights into the physiological roles of AβPP and its pathological
role in Alzheimer’s disease. The cytoplasmic domain of AβPP shares the evolutionarily conserved GYENPTY motif, which binds
to a number of adaptor proteins containing the phosphotyrosine interaction domain (PID). Among the PID-containing proteins,
this article focuses on four groups of adaptor proteins of AβPP: Fe65, X11, mDab1, and c-Jun N-terminal kinase-interacting protein 1b/islet-brain 1.
These two authors contributed equally to this study. 相似文献
16.
Alzheimer’s disease is a progressive neurodegenerative disorder that affects primarily learning and memory functions. There
is significant neuronal loss and impairment of metabolic functioning in the temporal lobe, an area believed to be crucial
for learning and memory tasks. Aggregated deposits of amyloid β-peptide may have a causative role in the development and progression
of AD. We review the cellular actions of Aβ and how they can contribute to the cytotoxicity observed in AD. Aβ causes plasma
membrane lipid peroxidation, impairment of ionmotive ATPases, glutamate uptake, uncoupling of a G-protein linked receptor,
and generation of reactive oxygen species. These effects contribute to the loss of intracellular calcium homeostasis reported
in cultured neurons. Many cell types other than neurons show alterations in the Alzheimer’s brain. The effects of Aβ on these
cell types is also reviewed. 相似文献
17.
The introduction of induced pluripotent stem (iPS) cells has been a milestone in the field of regenerative medicine and drug
discovery. iPS cells can provide a continuous and individualized source of stem cells and are considered to hold great potential
for economically feasible personalized stem cell therapy. Various diseases might potentially be cured by iPS cell-based therapy
including Parkinson’s disease, Alzheimer’s disease, Huntington disease, ischemic heart disease, diabetes and so on. Moreover,
iPS cells derived from patients suffering from unique incurable diseases can be developed into patient- and disease-specific
cell lines. These cells can be used as an effective approach to study the mechanisms of diseases, providing useful tools for
drug discovery, development and evaluation. The development of suitable methods for the culture and expansion of iPS cells
and their differentiated progenies make feasible modern drug discovery techniques such as high-throughput screening. Furthermore,
iPS cells can be applied in the field of toxicological and pharmacokinetics tests. This review focuses on the applications
of iPS cells in the field of pharmaceutical industry. 相似文献
18.
19.
Stem cells and neurodegenerative diseases 总被引:1,自引:0,他引:1
Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the de-velopment of old-aging society, the incidence of neurodegenerative diseases is on the increase. How-ever, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegen-erative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Hunt-ington’s disease and Amyotrophic lateral sclerosis/Lou Gehrig’s disease. 相似文献
20.
Lucatelli JF Barros AC Silva VK Machado Fda S Constantin PC Dias AA Hutz MH de Andrade FM 《Neurochemical research》2011,36(8):1533-1539
Alzheimer’s disease is a complex neurodegenerative disorder. Several genes have been suggested as Alzheimer’s susceptibility
factors, the apolipoprotein E (APOE) gene being an established susceptibility gene and the genes coding angiotensin-converting
enzyme (ACE) and apolipoprotein C1 (APOC1) being considered possible candidate genes for the disease. The objective of this
study was to investigate the association of ACE and APOC1 gene polymorphisms with susceptibility to Alzheimer’s disease and
dementia in general, both alone and combined with the APOE gene. Forty-seven patients with dementia in general (35 of them
with Alzheimer’s disease) and 85 controls were investigated. The haplotypes E*3/−317*ins and E*4/−317*ins of APOE/APOC1 genes were significantly more frequent in the groups with Alzheimer′s disease and dementia in general (P < 0.001). The frequency of the ACE*ins allele was also greater in the groups with Alzheimer’s disease and dementia in general (P = 0.022; P = 0.045), but genotype frequencies were only different in groups without the E*4/−317*ins haplotype (P = 0.012 for Alzheimer’s disease; P = 0.04 for dementia). Our data point to important genetic interactions involved in these diseases. 相似文献